On July 11, 2017, blinatumomab (Blincyto) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.1,2 Blinatumomab received accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory B-cell precursor ALL. The current labeling change reflects confirmation of clinical benefit required under the accelerated approval and expands the indication to include Ph-positive relapsed or refractory B-cell precursor ALL.
Supporting Efficacy Data
In the phase III TOWER trial, which confirmed the clinical benefit of the drug,2,3 405 patients with relapsed or refractory Ph-negative B-cell precursor ALL were randomized 2:1 to receive blinatumomab (n = 271) or standard-of-care chemotherapy (n = 134). Blinatumomab was given at 9 μg/d on days 1 to 7 and 28 μg/d on days 8 to 28 for cycle 1 in a 42-day cycle, at 28 μg/d on days 1 to 28 for cycles 2 to 5 in 42-day cycles, and at 28 μg/d on days 1 to 28 for cycles 6 to 9 in 84-day cycles. Standard-of-care chemotherapy included a regimen of fludarabine, cytarabine, and granulocyte colony-stimulating factor; high-dose cytarabine; high-dose methotrexate–based combinations; and clofarabine or clofarabine-based regimens.
OF NOTE
Blinatumomab carries boxed warnings for cytokine-release syndrome and neurologic toxicity, both of which may be life-threatening or fatal.
At an interim analysis, median overall survival was significantly improved with blinatumomab (7.7 vs 4.0 months, hazard ratio = 0.71, P = .012) on intent-to-treat analysis, and the study was stopped for early efficacy.
The inclusion of Ph-positive relapsed or refractory B-cell precursor ALL in the current indication was based on findings of durable responses in a single-arm multicenter study in 45 patients. Patients had disease resistant to or were intolerant of second-generation tyrosine kinase inhibitors and had imatinib-resistant disease. Complete remission with complete or partial hematologic recovery was achieved in 36% of patients. Median duration of remission was 6.7 months.
How It Works
Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell-adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, resulting in redirected lysis of CD19-positive cells.
How It Is Used
A treatment course consists of up to two cycles of blinatumo-mab induction followed by three cycles for consolidation and up to four additional cycles of continued therapy. Patients weighing ≥ 45 kg receive fixed doses, and those weighing < 45 kg receive doses adjusted for body surface area.
A single cycle of induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). A single cycle of continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval. If treatment is interrupted for an adverse event for ≤ 7 days, the same cycle should be continued to a total of 28 days of infusion including the days before and after the interruption. A new cycle should be started for interruption due to an adverse event lasting > 7 days.
For patients weighing ≥ 45 kg (< 45 kg), recommended dosing is as follows: induction cycle 1 = 9 μg/d (5 μg/m2/d, not to exceed 9 μg/d) on days 1 to 7, 28 μg/d (15 μg/m2/d, not to exceed 28 μg/d) on days 8 to 28, and no treatment on days 29 to 42; induction cycle 2 = 28 μg/d (15 μg/m2/d, not to exceed 28 μg/d) on days 1 to 28, and no treatment on days 29 to 42; consolidation cycles 3 to 5 = 28 μg/d (15 μg/m2/d, not to exceed 28 μg/d) on days 1 to 28, and no treatment on days 29 to 42; and continued therapy cycles 6 to 9 = 28 μg/d (15 μg/m2/d, not to exceed 28 μg/d) on days 1 to 28, and no treatment on days 29 to 84.
EXPANDED APPROVAL OF BLINATUMOMAB
- Blinatumomab (Blincyto) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.
- A treatment course consists of up to two cycles of blinatumomab induction followed by three cycles of consolidation and up to four additional cycles of continued therapy, with weight-based dosing.
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for ≥ 4 hours), supervision by a health-care professional or hospitalization is recommended. Premedication with dexamethasone is required. Adults should receive 20 mg of dexamethasone 1 hour prior to the first dose of each cycle, prior to a step dose, and when restarting infusion after an interruption of ≥ 4 hours. Pediatric patients should receive 5 mg/m2 of dexamethasone to a maximum dose of 20 mg prior to the first dose in the first cycle, prior to a step dose, and when restarting an infusion after an interruption of ≥ 4 hours in the first cycle.
Labeling provides specific instructions for blinatumomab infusion over 24 or 48 hours and for infusion over 7 days using bacteriostatic 0.9% sodium chloride (containing 0.9% benzyl alcohol), an option available for patients weighing ≥ 22 kg. However, this option should not be used in those weighing < 22 kg.
Treatment should be withheld for grade 3 cytokine-release syndrome, grade 3 neurologic toxicity, and other clinically relevant grade 3 adverse events. Labeling provides specific instructions for restarting therapy in these cases. Treatment should be permanently discontinued for grade 3 neurologic toxicity occurring at a dose of 9 μg (5 μg/m2) or if resolution takes > 7 days; other grade 3 adverse events requiring > 14 days for resolution; occurrence of > 1 seizure; and grade 4 cytokine-release syndrome or neurologic toxicity. Permanent treatment discontinuation should be considered for other grade 4 adverse events.
Safety Profile
In the trial in Ph-negative relapsed or refractory B-cell precursor ALL, the most common adverse events of any grade in the blinatumomab group (≥ 20%) were infections, pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse events occurred in 62%.
Grade ≥ 3 adverse events occurred in 87%. Adverse events led to discontinuation in 12% of patients, most commonly due to neurologic events and infections. Adverse events led to death in 16% of patients, with infections accounting for the majority of fatal events.
Blinatumomab carries boxed warnings for cytokine-release syndrome and neurologic toxicity, both of which may be life-threatening or fatal. It also carries warnings/precautions for infections, effects on ability to drive and use machines, pancreatitis, preparation and administration errors, and risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative.
Instructions for preparation (including admixing) and administration should be strictly followed. Blinatumomab prepared with preservative-free saline should be used for patients weighing < 22 kg. ■
REFERENCES
1. U.S. Food and Drug Administration: Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566708.htm. Accessed January 19, 2018.
2. Blincyto (blinatumomab) for injection prescribing information. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/125557s008lbl.pdf. Accessed January 19, 2018.
